Similarities in the HIV-1 and ASV Integrease Active Site Upon Metal Binding

Journal Article · Wed Apr 05 04:00:00 EDT 2000 · Biopolymers, 53(4):308-315

DOI:https://doi.org/10.1002/(SICI)1097-0282(20000405)53:4<308::AID-BIP3>3.0.CO;2-H· OSTI ID:15002306

Lins, Roberto D; Straatsma, TP; Briggs, J M

The HIV-1 integrase, which is essential for viral replication, catalyzes the insertion of viral DNA into the host chromosome thereby recruiting host cell machinery into making viral proteins. It represents the third main HIV enzyme target for inhibitor design, the first two being the reverse transcriptase and the protease. We report here a fully hydrated 2 ns molecular dynamics simulation performed using parallel NWChem3.2.1 with the AMBER95 force field. The HIV-1 integrase catalytic domain previously determined by crystallography (1B9D) and modeling including two Mg2+ ions placed into the active site based on an alignment against an ASV integrase structure containing two divalent metals (1VSH), was used as the starting structure. The simulation reveals a high degree of flexibility in the region of residues 140-149 even in the presence of a second divalent metal ion and a dramatic conformational change of the side chain of E152 when the second metal ion is present. This study shows similarities in the behavior of the catalytic residues in the HIV-1 and ASV integrases upon metal binding. The present simulation also provides support to the hypothesis that the second metal ion is likely to be carried into the HIV-1 integrase active site by the substrate, a strand of DNA.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (US)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 15002306
• Report Number(s): PNNL-SA-31137; KP1704020
• Journal Information: Biopolymers, 53(4):308-315, Journal Name: Biopolymers, 53(4):308-315 Journal Issue: 4 Vol. 53
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ALIGNMENT
CHROMOSOMES
CONFORMATIONAL CHANGES
CRYSTALLOGRAPHY
DNA
ENZYMES
FLEXIBILITY
HYPOTHESIS
MACHINERY
PROTEINS
RESIDUES
SIMULATION
TARGETS